Is BLK p.Asp458= (c.1374C>T) pathogenic?

BLK p.Asp458= (c.1374C>T) is classified Uncertain significance in BLK (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-30). Very rare (popmax 0.0011%, sas); Associated with maturity-onset diabetes of the young type 11.

What condition is associated with BLK p.Asp458= (c.1374C>T)?

BLK p.Asp458= (c.1374C>T) is associated with maturity-onset diabetes of the young type 11 (ClinVar).

How common is BLK p.Asp458= (c.1374C>T) in the general population?

BLK p.Asp458= (c.1374C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

How is MODY inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

BLK p.Asp458=

c.1374C>T · rs376977643 · VCV912038

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

maturity-onset diabetes of the young type 11

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.93	GERP -0.55, phastCons 0.35
Overall
CADD	11.16	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,986 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000498% 8/1,606,668 alleles · very rare exomes 7/1,454,398 · genomes 1/152,270 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,294
South Asiangrpmax	0.0011%	90,986
European (non-Finnish)	0.000509%	196,557

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: BLK
Protein: p.Asp458=
Coding: c.1374C>T
MANE Select: NM_001715
dbSNP: rs376977643
Type: single nucleotide variant
Location: chr8:11563964 (GRCh38)
Gene constraint: LOEUF 1.295 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89
Residue 458: the protein kinase domain

Full BLK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

maturity-onset diabetes of the young type 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MODY (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

BLK p.Asp458Glu Uncertain significance ★ ⚠ same residue
BLK p.Arg180His Uncertain significance ★★ ⚠ same condition
BLK p.Arg295Trp Uncertain significance ★★ same condition
BLK p.Arg298Gln Uncertain significance ★★ ⚠ same condition
BLK p.Gln226Pro Uncertain significance ★★ ⚠ same condition
BLK p.Gly451Ser Uncertain significance ★★ ⚠ same condition
BLK p.His55Arg Uncertain significance ★★ ⚠ same condition
BLK p.Ile338Thr Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/blk-p-asp458 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown